Bifunctional chiral organocatalytic compound having excellent enantioselectivity, preparation method therefor, and method for producing non-natural gamma-amino acid from nitro compound by using same

ABSTRACT

The present invention relates to a bifunctional chiral organocatalytic compound having excellent enantioselectivity, a preparation method therefor, and a method for producing a non-natural gamma amino acid from a nitro compound by using the chiral organocatalytic compound. According to the present invention, the bifunctional chiral organocatalytic compound having excellent enantioselectivity can be easily synthesized, gamma-amino acids with high optical selectivity can be obtained at a high yield by an economical and convenient method using the chiral organocatalytic compound, and various (R)-configuration gamma-amino acids, which are not present in nature, can be produced with high optical purity in large quantities by using a small amount of a catalyst, and therefore, the present invention can be widely utilized in various industrial fields including the pharmaceutical industry.

TECHNICAL FIELD

The present invention relates to a highly enantioselective chiralbifunctional organocatalyst, a method for preparing the chiralorganocatalyst, and a method for producing an unnatural γ-amino acidfrom a nitro compound using the chiral organocatalyst.

BACKGROUND ART

Amino acids are basic structural units for proteins and are divided intonatural amino acids and unnatural amino acids. Naturally occurring aminoacids are used as sweeteners and animal feed, whereas unnatural aminoacids corresponding to the isomers of natural amino acids are mainlyused as raw materials for medicines.

Optically pure amino acids are employed as ligands of asymmetriccatalysts or are widely used as starting materials or intermediatesnecessary for synthesizing a variety of pharmaceuticals and bioactivecompounds. Accordingly, optically pure amino acids are consideredindustrially very important.

Fermentation is known as a useful method for producing amino acids in aninexpensive and economical manner but is limited to the production ofnatural L-amino acids. Optically pure D-amino acids and unnatural aminoacids are currently produced by enzymatic resolution, opticalresolution, and chiral resolution. However, the prices of amino acidsproduced by the current resolution methods are 5-10 times higher thanthose of natural L-amino acids produced by fermentation because theresolution methods involve high production costs. Further, theresolution methods have difficulty in producing amino acids on a largescale.

Some methods have been reported for recognizing the chiralities ofchiral aminoalcohols and amino acids through imine bonds usingbinaphthol derivatives having an aldehyde group and converting L-aminoacids to the corresponding D forms, but there is still a need to developa method for producing an unnatural amino acid with highenantioselectivity in an economical and simple manner.

Under these circumstances, the present inventors have earnestly andintensively conducted research to solve the problems of the prior art,and as a result, found that even a small amount of a chiralorganocatalyst having a specific structure is sufficient for theproduction of various types of unnatural γ-amino acids in high opticalpurity. The present invention has been accomplished based on thisfinding.

DETAILED DESCRIPTION OF THE INVENTION Problems to be Solved by theInvention

Therefore, the present invention intends to provide a highlyenantioselective chiral bifunctional organocatalyst and a method forpreparing the chiral organocatalyst.

The present invention also intends to provide a method for producing anunnatural γ-amino acid from a nitro compound using the chiralorganocatalyst.

Means for Solving the Problems

The present invention provides a chiral organocatalyst represented byFormula 1:

The structure and substituents of the chiral organocatalyst representedby Formula 1 will be described below.

The present invention also provides a method for preparing the chiralorganocatalyst represented by Formula 1, including (a) reacting(R,R)-1,2-diphenylethylenediamine (DPEN) represented by Formula 2:

with a thiourea.

The present invention also provides a method for producing an unnaturalγ-amino acid, including (A) performing a Michael addition reaction of anα,β-unsaturated nitro compound with a malonic acid or malononitrile inthe presence of the chiral organocatalyst represented by Formula 1.

Effects of the Invention

The chiral bifunctional organocatalyst of the present invention ishighly enantioselective and can be easily synthesized. The use of thechiral organocatalyst enables the production of γ-amino acids with highenantioselectivity in high yield in an economical and simple manner. Inaddition, even a small amount of the chiral organocatalyst is sufficientfor mass production of various unnatural γ-amino acids with Rconfiguration in high optical purity. Therefore, the chiralorganocatalyst of the present invention can be widely utilized invarious industrial fields, including the pharmaceutical industry.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of substituted chiral organocatalystsaccording to exemplary embodiments of the present invention.

FIG. 2 shows a reaction scheme for the synthesis of a monoalkylatedthiourea catalyst according to one embodiment of the present invention.

FIG. 3 shows a reaction scheme for the synthesis of an arylated thioureacatalyst according to one embodiment of the present invention.

FIG. 4 shows a reaction scheme for Michael addition according to oneembodiment of the present invention.

FIG. 5 shows a reaction scheme for the production of an unnaturalγ-amino acid according to one embodiment of the present invention.

FIG. 6 shows a scheme for testing Michael addition reactions usingdifferent amounts of different chiral organocatalysts in differentsolvents according to exemplary embodiments of the present invention.

FIG. 7 shows a scheme for testing Michael addition reactions ofdifferent α,β-unsaturated nitro compounds according to exemplaryembodiments of the present invention (a) indicates the use of 0.4 ml ona 0.1 mmol scale).

FIG. 8 shows a reaction scheme for the production of an unnaturalγ-amino acid according to one embodiment of the present invention.

FIG. 9 shows a reaction scheme for the production of an unnaturalγ-amino acid according to one embodiment of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In general, the nomenclatureused herein is well known and commonly employed in the art.

One aspect of the present invention is directed to a chiralorganocatalyst represented by Formula 1:

wherein X is selected from O, S, P—R₃, and N—R₄ and R₁ to R₄ areidentical to or different from each other and are each independentlyselected from hydrogen, deuterium, substituted or unsubstituted C₁-C₃₀alkyl, substituted or unsubstituted C₃-C₃₀ cycloalkyl, substituted orunsubstituted C₂-C₃₀ heteroaryl, substituted or unsubstituted C₆-C₃₀aryl, substituted or unsubstituted C₆-C₃₀ arylamino, substituted orunsubstituted C₁-C₃₀ alkoxy, substituted or unsubstituted C₂-C₃₀alkoxycarbonyl, substituted or unsubstituted C₂-C₃₀ alkoxycarbonylamino,substituted or unsubstituted C₇-C₃₀ aryloxycarbonylamino, substituted orunsubstituted C₂-C₃₀ alkenyl, substituted or unsubstituted C₂-C₃₀alkynyl, substituted or unsubstituted C₃-C₄₀ silyl, substituted orunsubstituted C₃-C₄₀ silyloxy, substituted or unsubstituted C₁-C₃₀ acyl,substituted or unsubstituted C₁-C₂₀ acyloxy, and substituted orunsubstituted C₁-C₂ acylamino.

According to a preferred embodiment of the present invention, R₁ may behydrogen, 3-pentyl, Ph₂CH or 3,5-(CF₃)₂-PhCH₂ and R₂ may be phenyl,3,5-(CF₃)₂-Ph, p-tolyl, 4-CF₃-Ph, C₆F₅, 4-NO₂-Ph, 4-CN-Ph, 4-F-Ph,t-butyl or 3,5-(Me)₂-Ph.

A further aspect of the present invention is directed to a method forpreparing the chiral organocatalyst represented by Formula 1, including(a) reacting (R,R)-1,2-diphenylethylenediamine (DPEN) represented byFormula 2:

with a thiourea.

Another aspect of the present invention is directed to a method forproducing an unnatural γ-amino acid, including (A) performing a Michaeladdition reaction of an α,β-unsaturated nitro compound with a malonicacid or malononitrile in the presence of the chiral organocatalystrepresented by Formula 1.

According to a preferred embodiment of the present invention, theMichael addition reaction is performed in the absence or presence ofwater or an organic solvent, more preferably in the absence or presenceof water and affords a nitrostyrene.

The water is generally a solvent called water and may be, for example,cosmetic water, hexagonal water, hot vacuum water, distilled water,single-distilled water, double-distilled water, triple-distilled water,hydrogen water, extraction water, salt-containing water, drinking water,seawater, salt water, brackish water, mineral water, seltzer, bedrockwater, spring water, groundwater, deep water, soft water, tap water,hard water, ionized water, electrolyzed water or carbonated water but isnot limited thereto. The organic solvent is also not particularlylimited.

The method of the present invention may further include synthesizing apyrrolidinone from the Michael adduct wherein the pyrrolidinone isrepresented by Formula 3-1 or 3-2:

wherein R₇ and R₈ are identical to or different from each other and areeach independently selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₃₀ ketone, substituted or unsubstituted C₁-C₃₀ nitro,substituted or unsubstituted C₁-C₃₀ halogen, substituted orunsubstituted C₁-C₃₀ cyano, substituted or unsubstituted C₁-C₃₀ ester,substituted or unsubstituted C₁-C₃₀ alkyl, substituted or unsubstitutedC₃-C₃₀ cycloalkyl, substituted or unsubstituted C₂-C₃₀ heteroaryl,substituted or unsubstituted C₆-C₃₀ aryl, substituted or unsubstitutedC₆-C₃₀ arylamino, substituted or unsubstituted C₁-C₃₀ alkoxy,substituted or unsubstituted C₂-C₃₀ alkoxycarbonyl, substituted orunsubstituted C₂-C₃₀ alkoxycarbonylamino, substituted or unsubstitutedC₇-C₃₀ aryloxycarbonylamino, substituted or unsubstituted C₂-C₃₀alkenyl, substituted or unsubstituted C₂-C₃₀ alkynyl, substituted orunsubstituted C₃-C₄₀ silyl, substituted or unsubstituted C₃-C₄₀silyloxy, substituted or unsubstituted C₁-C₃₀ acyl, substituted orunsubstituted C₁-C₂₀ acyloxy, and substituted or unsubstituted C₁-C₂acylamino,

wherein R₇ and R₈ are as defined in Formula 3-1.

The method of the present invention may further include treating thepyrrolidinone with hydrochloric acid to produce an unnatural γ-aminoacid represented by Formula 4-1 or 4-2:

wherein R₉ is selected from hydrogen, deuterium, substituted orunsubstituted C₁-C₃₀ ketone, substituted or unsubstituted C₁-C₃₀ nitro,substituted or unsubstituted C₁-C₃₀ halogen, substituted orunsubstituted C₁-C₃₀ cyano, substituted or unsubstituted C₁-C₃₀ ester,substituted or unsubstituted C₁-C₃₀ alkyl, substituted or unsubstitutedC₃-C₃₀ cycloalkyl, substituted or unsubstituted C₂-C₃₀ heteroaryl,substituted or unsubstituted C₆-C₃₀ aryl, substituted or unsubstitutedC₆-C₃₀ arylamino, substituted or unsubstituted C₁-C₃₀ alkoxy,substituted or unsubstituted C₂-C₃₀ alkoxycarbonyl, substituted orunsubstituted C₂-C₃₀ alkoxycarbonylamino, substituted or unsubstitutedC₇-C₃₀ aryloxycarbonylamino, substituted or unsubstituted C₂-C₃₀alkenyl, substituted or unsubstituted C₂-C₃₀ alkynyl, substituted orunsubstituted C₃-C₄₀ silyl, substituted or unsubstituted C₃-C₄₀silyloxy, substituted or unsubstituted C₁-C₃₀ acyl, substituted orunsubstituted C₁-C₂₀ acyloxy, and substituted or unsubstituted C₁-C₂acylamino,

wherein R₉ is as defined in Formula 4-1.

The unnatural γ-amino acid of Formula 4-1 wherein R₉ is a phenyl groupmay be represented by Formula 5-1:

wherein R is hydrogen or halogen.

The unnatural γ-amino acid of Formula 4-2 wherein R₉ is a phenyl groupmay be represented by Formula 5-2:

wherein R is as defined in Formula 5-1.

The unnatural γ-amino acid of Formula 5-1 or 5-2 wherein R is hydrogenis phenibut as a sleep inducer. The unnatural γ-amino acid of Formula5-1 or 5-2 wherein R is chlorine is baclofen as a muscle relaxant.

MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in more detail with reference tothe following examples. It will be obvious to one of ordinary skill inthe art that these examples are provided for illustrative purposes onlyand are not intended to limit the scope of the present invention.Therefore, the substantial scope of the present invention is defined bythe appended claims and their equivalents.

Example 1: Preparation of Chiral Organocatalysts 1-1: Backbone Structureof Chiral Organocatalysts

(R,R)-1,2-diphenylethylenediamine (DPEN) of Formula 2 was used as abackbone structure for preparing chiral organocatalysts:

The backbone structure contains amino groups at the C-1 and C-2positions and has chirality at the C-1 and C-2 positions.

1-2: Preparation of Chiral Organocatalysts

The backbone structure was allowed to react with a thiourea to prepare achiral organocatalyst of Formula 1 (FIG. 1).

The chiral organocatalyst of Formula 1 has a structure in which the R₂moiety derived from the thiourea is attached to the backbone structure.When R₂ is an electron withdrawing group, the reaction yield ispredicted to be high in view of the characteristics of the R₂ moiety.The chiral organocatalyst is predicted to be highly enantioselective dueto the presence of the R₁-substituted amino group at the C-2 position.

Synthesis of Monoalkylated Thiourea Catalysts

To a solution of (R,R)-1,2-diphenylethylenediamine (1.0 equiv.) intoluene (0.1 M) was added a solution of 3-pentanone (1.1 equiv.) andMgSO₄. The mixture was refluxed for 48 h. Then, MgSO₄ was removed byfiltration through Celite and the mixture concentrated in vacuo. Afteraddition of NaBH₄ (4.0 equiv.) and ethanol, the resulting mixture wasstirred at room temperature for 1 h. The reaction was quenched with 1 NNaOH solution and the reaction mixture was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over MgSO₄,and concentrated in vacuo. The residue was purified by chromatography ona silica-gel column (methanol/methylene chloride, 1:20). Tomonoalkylated DPEN (1.0 equiv.) in CH₂Cl₂ (0.1 M) was added thiourea(1.1 equiv.). The mixture was stirred at room temperature for 1 h andpurified by flash column chromatography on silica gel with EA/hexane(1:5) to give the pure amide product (quantitative yield) as a white,foamy solid (FIG. 3).

Synthesis of Arylated Thiourea Catalysts

To a suspension of (R,R)-1,2-diphenylethylenediamine (1.0 equiv.) intoluene (0.5 M) was added thiourea (1.0 equiv.) at 0° C. The mixture wasstirred for 30 sec. The reaction mixture was concentrated in vacuo andpurified by flash column chromatography on silica gel withmethanol/methylene chloride (1:20). To thiourea-substituted DPEN (1.0equiv.) in CH₂Cl₂ (0.1 M) was added an alkyl ketone (1.1 equiv.). Themixture was stirred at room temperature for 1 h. After addition of NaBH₄(2.0 equiv.) and ethanol at 0° C., the resulting mixture was stirred atroom temperature for 1 h. The reaction mixture was filtered a pad ofcelite and extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by chromatography on a silica-gel column(methanol/methylene chloride, 1:20) to give the pure amide product(quantitative yield) as a brown, foamy solid (FIG. 3).

In FIG. 1 and Table 1, 1a indicates the chiral organocatalyst of Formula1 wherein R₁ is hydrogen and R₂ is phenyl (ph), 1b indicates the chiralorganocatalyst of Formula 1 wherein R₁ is hydrogen and R₂ is3,5-(CF₃)₂-Ph, 1e indicates the chiral organocatalyst of Formula 1wherein R₁ is 3-pentyl and R₂ is p-tolyl, 1d indicates the chiralorganocatalyst of Formula 1 wherein R₁ is 3-pentyl and R₂ is3,5-(CF₃)₂-Ph, 1e indicates the chiral organocatalyst of Formula 1wherein R₁ is 3-pentyl and R₂ is 4-CF₃-Ph, 1f indicates the chiralorganocatalyst of Formula 1 wherein R₁ is 3-pentyl and R₂ is C₆F₅, 1gindicates the chiral organocatalyst of Formula 1 wherein R₁ is 3-pentyland R₂ is 4-NO₂-Ph, 1h indicates the chiral organocatalyst of Formula 1wherein R₁ is 3-pentyl and R₂ is 4-NC-Ph, 1i indicates the chiralorganocatalyst of Formula 1 wherein R₁ is 3-pentyl and R₂ is 4-F-Ph, 1jindicates the chiral organocatalyst of Formula 1 wherein R₁ is Ph₂CH andR₂ is 3,5-(CF₃)₂-Ph, 1k indicates the chiral organocatalyst of Formula 1wherein R₁ is Ph₂CH and R₂ is t-butyl, 1l indicates the chiralorganocatalyst of Formula 1 wherein R₁ is Ph₂CH and R₂ is 4-CF₃-Ph, 1mindicates the chiral organocatalyst of Formula 1 wherein R₁ is3,5-(CF₃)₂-Ph-CH₂ and R₂ is 3,5-(CF₃)₂-Ph, and 1n indicates the chiralorganocatalyst of Formula 1 wherein R₁ is 3,5-(CF₃)₂-Ph-CH₂ and R₂ is3,5-(CF₃)₂-Ph.

TABLE 1 Chiral organocatalyst Chemical name 1a1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-phenylthiourea 1b1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-[3,5-Bis(trifluoromethyl)phenyl]thiourea 1c1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(p-tolyl)thiourea1d1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea 1e1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-[4-(trifluoromethyl)phenyl]thiourea 1f1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(perfluorophenyl)thiourea 1g1-(4-Nitrophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea 1h1-(4-Cyanophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea 1i1-(4-Fluorophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea 1j1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea 1k1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-tert-butylthiourea1l 1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(4-(trifluoromethyl)phenyl)th-iourea 1m1-((1R,2R)-2-(3,5-bis(trifluoromethyl)benzylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea 1n1-((1R,2R)-2-(3,5-dimethylbenzylamino)-1,2-diphenylethyl)-3-(3,5-dimethylphenyl)th-iourea

The results of NMR analysis for the chiral organocatalysts 1a to 1n areas follows:

(1a) 94% yield; [α]_(D) ²⁰=+62.0 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.76 (s, 1H), 7.54˜7.19 (m, 15H), 5.54 (s, 1H), 4.42 (d, 1H,J=5 Hz), 1.35 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 182.09, 134.48,133.93, 129.89, 128.70, 128.10, 127.91, 127.15, 126.94, 126.82, 126.74,126.23, 125.59, 125.24, 122.98, 63.07, 59.09; IR (KBr) 3287.86, 3027.84,1521.63, 1241.99, 1072.28, 939.20, 698.13 cm⁻¹; HRMS (FAB⁺) forC₂₁H₂₂N₃S [M+H]⁺ Calcd: 348.4918, Found: 348.1534.

(1b) [α]_(D) ²⁵=+13.5 (c 1.00, CH₃Cl); ¹H NMR (300 MHz, DMSO-d₆) δ 10.70(s, 1H), 8.32 (s, 2H), 7.71 (s, 1H), 7.22˜7.43 (m, 13H), 5.57 (d, J=3Hz, 1H), 4.44 (d, J=3 Hz, 1H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 180.80,143.41, 142.67, 130.94, 130.62, 128.81, 128.61 127.75, 127.57, 127.51,125.25, 122.54, 121.68, 116.40, 63.86, 60.06 ppm; IR (KBr) 3305, 3032,2963, 1652, 1601, 1557, 1383, 1277, 1262, 803, 700 cm⁻¹; HRMS (FAB⁺) forC₂₂H₂N₄S [M+H]⁺ Calcd: 372.1487, Found: 372.1456.

(1c) 86% yield; [α]_(D) ²⁰=+0.19 (c=1.00, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 9.76 (s, 1H), 7.89 (d, J=7.0 Hz, 1H), 7.32˜7.18 (m, 14H),5.44 (s, 1H), 4.08 (d, J=5.1 Hz, 1H), 2.29 (s, 2H), 2.02 (s, 1H), 1.39(s, 1H), 1.20˜1.06 (m, 4H), 0.68 (t, J=7.5 Hz, 3H), 0.41 (t, J=7.1 Hz,3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.04, 141.83, 141.55, 136.71,134.88, 130.03, 128.67, 128.51, 127.49, 127.40, 124.67, 64.28, 63.77,55.84, 26.71, 24.02, 21.20, 10.94, 8.30; IR (KBr) 3180.2, 2958.4,1948.8, 1510.1, 1240.1, 821.6, 700.1, 565.1 cm⁻¹; HRMS (FAB⁺) forC₂₇H₃₄N₃S [M+H]⁺ Calcd: 432.2473, Found: 432.6537, pattern 432.5, 345.3,266.4, 176.3, 106.01.

(1d) 90% yield; [α]_(D) ²⁰=+0.31 (c=0.11, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 10.5 (br, 1H), 8.30 (s, 2H), 7.74 (s, 1H), 7.40˜7.19 (m,10H), 5.57 (br, 1H), 4.18 (d, J=4.9 Hz, 1H), 2.09 (m, 1H), 1.24˜1.20 (m,4H), 0.75 (t, J=7.1 Hz, 3H), 0.50 (t, J=6.0 Hz, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 181.10, 142.49, 140.88, 130.96, 130.64, 128.70, 128.59,128.56, 127.60, 125.22, 122.52, 122.19, 116.70, 64.34, 63.62, 56.48,26.64, 23.90, 10.98, 8.54; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6,1135.9, 885.2, 700.1 cm⁻¹; HRMS (FAB⁺) for C₂₈H₃₀F₆N₃S [M+H]⁺ Calcd:554.2065, Found: 554.2065.

(1e) 88% yield; [α]_(D) ²⁰=+45.5 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 10.2 (br s, 1H), 8.41 (br s, 1H), 7.79 (d, J=8.0 Hz, 2H),7.64 (d, J=8.5 Hz, 2H), 7.35˜7.15 (m, 10H), 5.53 (br s, 1H), 4.13 (d,J=5.5 Hz, 1H), 2.07 (m, 1H), 1.30˜1.15 (m, 4H), 0.73 (t, J=7.1 Hz, 3H),0.49 (t, J=6.9 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 180.91, 143.97,141.18, 128.64, 128.52, 127.69, 127.48, 126.29, 122.41, 64.43, 63.71,56.32, 26.68, 23.98, 10.98, 8.53; IR(KBr) 3205.3, 2962.3, 1945.9,1741.5, 1517.8, 1324.9, 1245.9, 1066.5, 840.9, 700.1, 597.9 cm⁻¹;HRMS(FAB⁺) for C₂₇H₃₁F₃N₃S[M+H]⁺ Calcd: 486.2191, Found: 486.2190.

(1f) 89% yield; [α]_(D) ²⁰=+80.4 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 9.47 (s, 1H), 8.61 (s, 1H), 7.30˜7.15 (m, 10H), 5.48 (br s,1H), 4.13 (d, J=6.1 Hz, 1H), 2.08 (m, 1H), 1.54 (br, 1H), 1.30˜1.14 (m,4H), 0.74 (t, J=7.4 Hz, 3H), 0.55 (t, J=6.3 Hz, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 183.63, 145.82, 143.43, 141.90, 140.77, 139.01, 138.84,136.56, 129.39, 128.61, 128.43, 127.68, 127.60, 115.93, 64.77, 64.53,56.37, 26.72, 24.16, 10.86, 8.58; IR (KBr) 3299.8, 2964.2, 1525.5,1344.2, 1145.6, 991.3, 912.2, 700.1, 605.6 cm⁻¹; HRMS (FAB⁺) forC₂₆H₂₇F₅N₃S [M+H]⁺ Calcd: 508.1846, Found: 508.1848.

(1g) 89% yield; [α]_(D) ²⁰=+37.7 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 10.5 (s, 1H), 8.16 (m, 2H), 7.90 (d, J=9.1 Hz, 2H), 7.37˜7.15(m, 10H), 5.54 (br s, 1H), 4.16 (d, J=5.5 Hz, 1H), 2.07 (m, 1H),1.30˜1.15 (m, 4H), 0.75 (t, J=7.4 Hz, 3H), 0.50 (t, J=7.4 Hz, 3H); ¹³CNMR (100 MHz, DMSO-d₆) δ 180.51, 146.95, 142.46, 141.92, 140.92, 128.68,128.56, 127.72, 125.16, 120.92, 64.35, 63.80, 56.35, 55.59, 26.70,23.96, 11.03, 8.61; IR (KBr) 3330.5, 2960.2, 2599.6, 2456.4, 2345.0,1951.6, 1743.3, 1496.5, 1346.1, 1110.8, 1072.2, 852.4, 700.0, 586.3cm⁻¹; HRMS (FAB⁺) for C₂₆H₃₁N₄O₂S [M+H]⁺ Calcd: 463.2168, Found:463.2165.

(1h) 69% yield; [α]_(D) ²⁰=+55.5 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 10.3 (br s, 1H), 8.54 (br s, 1H), 7.84˜7.72 (m, 4H),7.35˜7.17 (m, 10H), 5.54 (br s, 1H), 4.14 (d, J=5.2 Hz, 1H), 2.07 (br s,1H), 1.56 (br s, 1H), 1.21 (m, 4H), 0.74 (t, J=7.4 Hz, 3H), 0.49 (t,J=6.9 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 180.62, 144.83, 141.92,141.05, 133.40, 128.67, 128.33, 127.68, 127.64, 127.51, 121.76, 119.76,105.41, 64.41, 63.72, 60.43, 56.33, 26.74, 23.98, 21.42, 14.74, 11.02,8.56; IR (KBr) 3317.0, 2960.2, 2360.4, 2225.5, 1949.7, 1739.5, 1508.1,1315.2, 1176.4, 1072.2, 837.0, 700.0, 545.8 cm⁻¹; HRMS (FAB⁺) forC₂₇H₃₁N₄S [M+H]⁺ Calcd: 443.2269, Found: 443.2271.

(1i) 84% yield; [α]_(D) ²⁰=+17.9 (c=0.02, CH₂Cl₂); ¹H NMR (300 MHz,DMSO-d₆) δ 9.83 (s, 1H), 8.00 (d, J=6.7 Hz, 1H), 7.48˜7.43 (m, 2H),7.31˜7.16 (m, 11H), 5.46 (br s, 1H), 4.09 (d, J=5.22 Hz, 1H), 2.03 (brs, 1H), 1.44 (br s, 1H), 1.14 (m, 4H), 0.70 (t, J=10.1, 3H), 0.44 (t,J=7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.42, 161.03, 158.62,141.90, 141.44, 135.97, 128.65, 128.51, 127.57, 127.42, 126.49, 116.13,115.90, 64.39, 63.76, 56.03, 26.72, 24.02, 10.98, 8.39; IR (KBr) 3193.7,2962.3, 1889.9, 1511.9, 1218.8, 848.6, 701.9, 555.42 cm⁻¹; HRMS (FAB⁺)for C₂₆H₃₁FN₃S[M+H]⁺ Calcd: 436.6172, Found: 436.2223. pattern 436.5,349.3, 266.4, 176.3, 106.1.

(1j) 95% yield; [α]_(D) ²⁰=+0.39 (c=0.16, CH₂Cl₂); ¹H NMR (400 MHz,DMSO-d₆) δ 7.82˜7.09 (m, 23H), 5.72 (s, 1H), 3.98 (s, 1H), 3.35 (s, 1H),2.47 (br, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.06, 156.63, 153.35,143.36, 142.03, 141.31, 138.68, 129.48, 129.34, 126.90, 125.59, 123.65,122.55, 122.14, 70.83, 65.14, 55.50; IR (KBr) 3239.9, 2964.2, 1471.5,1278.6, 1135.9, 885.2, 700.1 cm⁻¹; HRMS (EI⁺) for C₂₈H₃₀F₆N₃S [M+H]⁺Calcd: 649.1986, Found: 649.1932.

(1k) 93% yield; [α]_(D) ²⁰=+115 (c 0.17, CH₂Cl₂); ¹H NMR (400 MHz,DMSO-d₆) δ 7.61˜7.03 (m, 20H), 4.13 (q, 3H), 2.92 (s, 9H), 1.76 (br,2H); IR(KBr) 3679.6, 2978.4, 1414.3, 1262.8, 1059.4, 886.1, 735.0 cm⁻¹;HRMS(EI⁺) for C₃₂H₃₅N₃S [M+H]⁺ Calcd: 493.2552, Found: 493.2587.

(1k) 89% yield; [α]_(D) ²⁰=+124 (c 0.10, CH₂C₁₂); ¹H NMR (300 MHz,DMSO-d₆) δ 9.44 (br, 1H), 7.77˜7.10 (m, 26H), 4.90 (s, 1H), 4.82 (s,2H), 1.92 (s, 1H); IR(KBr) 3679.5, 3352.2, 2985.3, 1402.4, 1265.9,1065.7, 726.8 cm⁻¹; HRMS(FAB⁺) for C₃₅H₃F₃N₃S [M+H]⁺ Calcd: 581.2113,Found: 581.2133.

(1m) 93% yield; [α]_(D) ²⁰=+0.45 (c=0.11, CH₂Cl₂); ¹H NMR (500 MHz,DMSO-d₆) δ 7.61 (br, 3H), 7.39˜7.29 (m, 16H), 4.54 (s, 4H); ¹³C NMR (100MHz, DMSO-d₆) δ 171.58, 157.99, 142.12, 131.46, 134.14, 129.17, 127.28,125.67, 122.96, 112.29, 89.59, 89.05, 84.78; IR (KBr) 3032.6, 2871.3,1663.5, 1386.6, 1275.9, 1117.5, 930.2, 700.2 cm⁻¹; HRMS (FAB⁺) forC₃₂H₂₃F₁₂N₃S [M+H]⁺ Calcd: 709.1421, Found: 709.1428.

(1n) 89% yield; [α]_(D) ²⁰=+112 (c 0.13, CH₂Cl₂); ¹H NMR (500 MHz,DMSO-d₆) δ 7.38 (t, 6H), 7.32 (d, 2H), 7.27 (d, 4H), 7.00 (s, 4H), 4.54(s, 4H), 2.21 (s, 12H), 1.25 (br, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ167.08, 157.71, 156.95, 143.07, 138.05, 131.22, 129.00, 128.93, 127.09,127.03, 123.43, 118.64, 112.63, 70.28, 68.05, 67.38, 21.63; IR(KBr)3155.0, 2960.2, 2360.4, 1951.6, 1735.6, 1469.5, 1294.0, 1241.9, 1006.7,837.0, 700.0, 572.8 cm⁻¹; HRMS(FAB⁺) for C₂₆H₃₀F₂N₃S[M+H]⁺ Calcd:454.2129, Found: 454.2133.

Example 2: Production of Unnatural γ-Amino Acids Using the ChiralOrganocatalysts

A Michael addition reaction of an α,β-unsaturated nitro compound with adialkyl malonate or malononitrile was performed using each of the chiralorganocatalysts prepared in Example 1. The Michael addition reaction wascompleted within 24 h, affording a nitrostyrene in a yield of 91-99% andan enantioselectivity of 91-99%. Applied compounds were synthesizedusing the Michael adduct. NiCl₂.6H₂O.NaBH₄ was added to a4-Cl-substituted nitrostyrene as the Michael adduct. As a result of thereaction, the nitro group was reduced and cyclization occurred to form a2-pyrrolidinone having an ethyl ester group, represented by Formula 3-1or 3-2:

As a result of the subsequent reaction, the carboxyl group was removedto form a 2-pyrrolidinone. The 2-pyrrolidinone was treated with 6 N HClto synthesize an unnatural γ-amino acid of Formula 4-1 or 4-2:

The unnatural γ-amino acid of Formula 4-1 or 4-2 wherein R₉ isCl-substituted phenyl is baclofen and the unnatural γ-amino acid ofFormula 4-1 or 4-2 wherein R₉ is unsubstituted phenyl is phenibut (FIGS.4 and 5).

Specifically, trans-β-nitrostyrene (1.0 equiv.) as the α,β-unsaturatednitro compound was mixed with malononitrile (2.0 equiv.) in the presenceof the chiral organocatalyst 1m (0.1-0.001 mol %) prepared in Example 1in water (0.4 ml) as a solvent. The mixture was stirred at roomtemperature. The reaction conversion was monitored by TLC. Aftercompletion of the reaction, 6 N HCl was added to the reaction mixture,followed by heating at 65° C. for 2 h. The resulting mixture was cooledto room temperature, added with a dialkyl carbonate (1.5 equiv.), andheated with stirring at 100° C. for 3 h. Thereafter, the homogeneousreaction mixture was cooled to room temperature, poured into a 10%aqueous solution of NaHCO₃, and added with ethyl acetate (0.2 ml). Thissolution was washed twice with water (2×1.0 mL), dried over magnesiumsulfate, and concentrated to afford the desired product. The product waspurified by chromatography on a silica-gel column (hexane/methylenechloride, 2:1) (2a-2m in Table 2). Under an argon atmosphere, NaBH₄ (10equiv.) was added to a suspension of the Michael adduct (1.0equiv., >99% ee) and NiCl₂.6H₂O (1.0 equiv.) in MeOH (8.0 ml) at 0° C.The mixture was stirred at room temperature for 7.5 h. The reaction wasquenched with NH₄Cl and the reaction mixture was diluted with CHCl₃. Theorganic layer was separated, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (MeOH/CHCl_(3=1/20) as the eluent) to afford the desiredproduct as a colorless powder (2n and 2o in Table 2). The product 2n or2o (1.0 equiv.) in 6 N HCl (2.7 ml) was refluxed at 100° C. After 12 h,the reaction mixture was concentrated in vacuo to afford(R)-(−)-baclofen and phenibut (2p and 2q in Table 2, 97-98%) ascolorless solids.

TABLE 2 Product Chemical name 2a (R)-Dimethyl2-(2-nitro-1-phenylethyl)malonate 2b (R)-Diethyl2-(2-nitro-1-phenylethyl)malonate 2c (R)-Diisopropyl2-(2-nitro-1-phenylethyl)malonate 2d (R)-Dipropyl2-(2-nitro-1-phenylethyl)malonate 2e(R)-Benzyl-2-carbobenzyloxy-4-nitro-3-phenylbutyrate 2f (R)-dibutyl2-(2-nitro-1-phenylethyl)malonate 2g (R)-Diethyl2-[1-(4-bromophenyl)-2-nitroethyl]malonate 2h (R)-diethyl2-(1-(4-chlorophenyl)-2-nitroethyl)malonate 2i (R)-Diethyl2-[2-nitro-1-(p-tolyl)ethyl]malonate 2j (R)-Diethyl2-[1-(4-hydroxyphenyl)-2-nitroethyl]malonate 2k (R)-Diethyl2-[1-(4-methoxyphenyl)-2-nitroethyl]malonate 2l (R)-Diethyl2-[1-(2-methoxyphenyl)-2-nitroethyl]malonate 2m (R)-Diethyl2-[1-(furan-2-yl)-2-nitroethyl]malonate 2n (R)-ethyl2-oxo-4-phenylpyrrolidine-3-carboxylate 2o (R)-Ethyl4-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylate 2p(R)-4-amino-3-phenyl-butanoic acid hydrochloride 2q(R)-4-Amino-[3-(4-chlorophenyl)]-butanoic acid hydrochloride 3a(S)-4-Nitro-1,3-diphenyl-butan-1-one 3b(S)-3-(4-Chlorophenyl)-4-nitro-1-phenylbutan-1-one 3c(S)-4-nitro-1-phenyl-3-(p-tolyl)butan-1-one 3d(S)-3-(4-Bromophenyl)-4-nitro-1-phenylbutan-1-one 3e(S)-3-(4-Chlorophenyl)-4-nitro-1-phenylbutan-1-one 3f(S)-3-(4-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one 3g(S)-3-(2-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one 3h(S)-3-(Furan-2-yl)-4-nitro-1-phenylbutan-1-one 3i (S)-Phenyl4-nitro-3-phenylbutanoate 3j (S)-Phenyl3-(4-chlorophenyl)-4-nitrobutanoate 3k (S)-4-Phenylpyrrolidin-2-one 3l(R)-4-Phenylpyrrolidin-2-one 3m (S)-4-(4-Chlorophenyl)pyrrolidin-2-one3n (R)-4-(4-Chlorophenyl)pyrrolidin-2-one 3o(S)-4-Amino-3-phenylbutanoicacid 3p(S)-4-Amino-3-(4-chlorophenyl)butanoic acid 3q(S)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide 3r(R)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide 3s(S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide

The analytical results of the products 2a to 2q and 3a to 3s are asfollows:

(2a) [α]_(D) ²⁰=−1.98 (c 1.33, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃)δ7.40˜7.15 (m, 5H), 5.15˜5.03 (m, 1H), 4.93 (dd, J=4.5, 12.8 Hz, 1H),4.88˜4.76 (m, 2H), 4.20 (td, J=4.5, 9.5 Hz, 1H), 3.76 (d, J=9.5 Hz, 1H),1.24 (d, J=6.1 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.01 (d, J=6.4 Hz, 3H)ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.1, 166.4, 136.3, 128.9, 128.3,128.2, 77.9, 69.9, 69.5, 55.1, 42.9, 21.5, 21.4, 21.19, 21.17 ppm;IR(KBr) 3030, 2985, 1727, 1557 cm⁻¹; HRMS(ESI) for C₁₃H₁₆N₁O₆[M+H]⁺Calcd: 282.09721, Found: 282.09726; HPLC [Chiralcel AD-H,hexane/2-propanol=95/5, 1.0 mL/min, k=254 nm, retention times: (major)23.3 min, (minor) 38.0 min].

(2b) [α]_(D) ²⁰=−4.61 (c 0.23, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃)δ7.30˜7.20 (m, 5H), 4.93 (dd, J=4.6, 13.1 Hz, 1H), 4.86 (dd, J=9.2, 13.1Hz, 1H), 4.24˜4.17 (m, 3H), 3.98˜3.97 (q, J=7.2 Hz, 2H), 3.81˜3.79 (d,J=9.5 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H) ppm; ¹³CNMR (100 MHz, CDCl₃) δ 167.4, 166.7, 136.2, 128.8, 128.2, 127.9, 77.6,62.0, 61.8, 54.9, 42.9, 13.9, 13.6 ppm; IR(KBr) 2989, 2938, 1731, 1557cm⁻¹; HRMS(ESI) for C₁₅H₂₀N₁O₆[M+H]⁺ Calcd: 310.12851, Found: 310.12936;HPLC [Chiralcel AD-H, hexane/ethanol=90/10, 1.0 mL/min, k=254 nm,retention times: (major) 11.5 min, (minor) 15.3 min].

(2c) [α]_(D) ²⁰=−1.24 (c 1.00, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃)δ7.32˜7.22 (m, 5H), 5.10 (dd, J=5.0, 13.1 Hz, 1H), 4.91˜4.979 (m, 3H),4.21˜4.19 (m, 1H), 1.25 (d, J=2.0 Hz, 6H), 1.07 (dd, J=2.0, 2.0 Hz, 6H)ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.27, 166.54, 136.47, 129.07, 128.34,127.9, 78.15, 70.15, 69.75, 55.35, 43.14, 21.80, 21.67, 21.48 ppm;IR(KBr) 3029, 2956, 1737, 1558 cm⁻¹; HRMS(ESI) for C₁₇H₂₄N₁O₆[M+H]⁺Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H,hexane/2-propanol=95/5, 1.0 mL/min, λ=254 nm, retention times: (major)14.8 min, (minor) 34.4 min].

(2d) [α]_(D) ²⁰=−1.73 (c 0.10, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ7.31˜7.22 (m, 5H), 4.92˜4.87 (t, J=5.0, 9.5 Hz, 2H), 4.24 (m, 1H),4.15˜4.09 (m, 2H), 3.92˜3.83 (dd, s, J=6.6 9.7 Hz, 3H), 1.68˜1.61 (m,2H), 1.49˜1.42 (m, 2H), 0.93˜0.88 (t, J=7.4, 7.4 Hz, 3H), 0.82˜0.77 (t,J=7.4, 7.4 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.79, 167.17,136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16,21.97, 21.81, 10.48 ppm; IR(KBr) 3029, 2956, 1737, 1558 cm⁻¹; HRMS(ESI)for C₁₇H₂₄N₁O₆[M+H]⁺ Calcd: 338.15981 Found: 338.16336; HPLC [ChiralcelAD-H, hexane/2-propanol=95/5, 1.0 mL/min, λ=254 nm, retention times:(major) 18.4 min, (minor) 38.9 min].

(2e) [α]_(D) ²⁰=−3.25 (c 0.10, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ7.33˜7.25 (m, 10H), 7.17˜7.07 (m, 5H), 5.16 (d, 1H, J=12.2 Hz), 5.18 (d,1H, JAB=12.2 Hz), 4.93 (S, 1H), 4.84˜4.82 (m, 2H), 4.28˜4.22 (q, 1H),3.94 (d, 1H, 9.3 Hz); 13C NMR (100 MHz, CDCl3) δ 167.39, 166.78, 136.14,134.85, 129.25, 128.90, 128.15, 77.63, 68.04, 67.86, 55.14, 43.16 ppm;IR(KBr) 3068, 3036, 2963, 1736, 1558, 1498, 1456, 1378, 1326, 1286,1217, 1156, 1003, 975, 908, 562 cm⁻¹; HRMS(EI) for C₂₅H₂₃N₁O₆[M+H]⁺Calcd: 433.1525 Found: 433.1525; HPLC [Chiralcel AD-H,hexane/2-propanol=70/30, 1.0 mL/min, λ=254 nm, retention times: (major)26.0 min, (minor) 24.1 min].

(2f) [α]_(D) ²⁰=−2.55 (c 0.10, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ7.31˜7.22 (m, 5H), 4.92˜4.87 (t, J=5.0, 9.5 Hz, 2H), 4.24 (m, 1H),4.15˜4.09 (m, 2H), 3.92˜3.83 (dd, s, J=6.6 9.7 Hz, 3H), 1.68˜1.61 (m,2H), 1.49˜1.42 (m, 2H), 0.93˜0.88 (t, J=7.4, 7.4 Hz, 3H), 0.82˜0.77 (t,J=7.4, 7.4 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.79, 167.17,136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16,21.97, 21.81, 10.48 ppm; HRMS(EI) for C₁₇H₂₄N₁O₆ [M+H]⁺ Calcd: 338.15981Found: 338.16336; HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, 1.0mL/min, λ=254 nm, retention times: (major) 18.4 min, (minor) 38.9 min].

(2g) 77% yield; [α]_(D) ²⁰=−3.56 (c 2.33, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.44˜7.42 (d, J=8.5 Hz, 2H), 7.13˜7.11 (d, J=8.2 Hz, 2H),4.88˜4.81 (m, 2H), 4.22˜4.16 (m, 3H), 4.04˜3.97 (q, J=7.1, 6.9 Hz, 2H),3.78˜3.75 (d, J=9.4 Hz, 1H), 1.26˜1.21 (t, J=7.2, 7.1 Hz, 3H), 1.08˜1.03(t, J=7.1, 7.1 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.42, 166.83,135.52, 132.29, 130.00, 122.62, 77.55, 62.50, 62.26, 54.86, 42.60,14.17, 13.99 ppm; IR (KBr) 2983, 2950, 1732, 1556, 1490, 1445 cm⁻¹HRMS(ESI) for C₁₅H₁₉N₁O₆Br[M+H]⁺ Calcd: 388.03903 Found: 388.04495; HPLC[Chiralcel AD-H, hexane/ethanol=95/5, 1.0 mL/min, λ=254 nm, retentiontimes: (major) 35.9 min, (minor) 44.4 min].

(2h) [α]_(D) ²⁰=−0.24 (c 0.43, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ7.29˜7.17 (dd, J=20.6, 8.2 Hz, 4H), 4.88˜4.81 (m, 2H), 4.23˜4.16 (m,3H), 4.04˜3.97 (q, J=7.1, 7.1 Hz, 2H), 3.78˜3.75 (d, J=9.3 Hz, 1H),1.26˜1.21 (t, J=7.1, 7.2 Hz, 3H), 1.08˜1.03 (t, J=7.2, 6.8 Hz, 3H) ppm;¹³C NMR (100 MHz, CDCl₃) δ 167.44, 166.83, 134.98, 134.46, 129.69,129.32, 77.63, 62.49, 62.23, 54.92, 42.55, 14.15, 13.97 ppm; IR (KBr)2984, 1733, 1557, 1478, 1445, 1371 cm-1 HRMS(ESI) for C₁₅H₉N₁O₆Cl[M+H]⁺Calcd: 344.08954 Found: 344.09119; HPLC [Chiralcel AD-H,hexane/ethanol=90/10, 1.0 mL/min, λ=254 nm, retention times: (major)17.9 min, (minor) 24.1 min].

(2i) 60% yield; [α]_(D) ²⁰=−1.56 (c 1.33, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.09 (d, J=15.2 Hz, 4H), 4.89˜4.78 (m, 2H), 4.22˜4.14 (m, 3H),4.01˜3.96 (q, J=7.0, 7.1 Hz, 2H), 3.79 (d, J=9.3 Hz, 1H), 2.27 (s, 3H),1.25˜1.22 (t, J=7.1, 7.0 Hz, 3H), 1.06˜1.02 (t, J=7.1, 8.6 Hz, 3H) ppm;¹³C NMR (100 MHz, CDCl₃) δ 167.74, 167.08, 138.27, 138.23, 133.30,129.80, 128.05, 78.00, 62.32, 62.06, 55.24, 42.84, 21.28, 14.18, 13.97ppm; IR(KBr) 3030, 2987, 1732, 1612, 1557 cm⁻¹; HRMS(ESI) for C₁₆H₂₂N₁O₆[M+H]⁺ Calcd: 324.14416 Found: 324.14648; HPLC [Chiralcel AD-H,hexane/ethanol=98/2, 1.0 mL/min, λ=254 nm, retention times: (major) 36.0min, (minor) 42.8 min].

(2j) 40% yield; [α]_(D) ²⁰=−1.56 (c=0.50, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.09˜7.06 (d, J=8.3 Hz, 2H), 6.72˜6.70 (d, J=8.2 Hz, 2H), 5.63(br, 1H), 4.91˜4.74 (m, 2H), 4.25˜4.12 (m, 3H), 4.05˜3.98 (q, J=7.1, 6.8Hz, 2H), 3.79 (d, J=9.7 Hz, 1H), 1.29˜1.24 (t, J=7.1, 6.6 Hz, 3H),1.09˜1.05 (t, J=7.1, 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.74,167.28, 155.88, 129.54, 128.06, 78.17, 62.44, 62.23, 55.29, 42.53,29.92, 14.20, 14.00 ppm; HRMS(ESI) for C₁₅H₂₀N₁O₇[M+H]⁺ Calcd: 326.12343Found: 326.12903; HPLC [Chiralcel AD-H, hexane/ethanol=90/10, 1.0mL/min, λ=254 nm, retention times: (major) 20.4 min, (minor) 50.6 min].

(2k) 47% yield; [α]_(D) ²⁰=−1.37 (c 0.80, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.16˜7.13 (d, J=8.5 Hz, 2H), 6.84˜6.81 (d, J=8.8 Hz, 2H),4.87˜4.80 (m, 2H), 4.24˜4.16 (m, 3H), 4.04˜3.97 (q, J=7.1, 7.1 Hz, 2H),3.79˜3.78 (d, J=2.7 Hz, 1H), 3.76 (s, 3H), 1.28˜1.23 (t, J=7.1, 7.2 Hz,3H), 1.08˜1.03 (t, J=7.1, 7.1 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ167.73, 167.08, 159.61, 129.36, 128.17, 114.48, 78.12, 62.34, 62.06,55.42, 55.30, 42.53, 14.19, 14.01 ppm; IR(KBr) 2988, 2936, 2904, 1730,1612, 1552 cm-1 HRMS(ESI) for C₁₆H₂₂N₁O₇[M+H]⁺ Calcd: 340.13908 Found:340.13901; HPLC [Chiralcel AD-H, hexane/ethanol=90/10, 1.0 mL/min, λ=254nm, retention times: (major) 23.8 min, (minor) 39.5 min].

(2l) 51% yield; [α]_(D) ²⁰=−7.08 (c 1.30, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.26˜7.21 (m, 1H), 7.15˜7.12 (m, 1H), 6.87˜6.83 (m, 2H),5.06˜4.98 (dd, J=3.6, 1.1 Hz, 1H), 4.89˜4.83 (dd, J=3.6, 1.1 Hz, 1H),4.37˜4.34 (m, 1H), 4.24˜4.12 (m, 3H), 3.97˜3.90 (q, J=7.2, 7.2 Hz, 2H),3.85 (s, 3H), 1.28˜1.23 (t, J=7.1, 6.9 Hz, 3H), 1.01˜0.96 (t, J=7.2, 7.1Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 168.14, 167.41, 157.62, 131.09,129.83, 123.87, 120.96, 111.27, 76.40, 62.18, 61.77, 55.62, 52.89,40.74, 14.20, 13.94 ppm; IR (KBr) 2984, 2939, 2908, 1732, 1613, 1556cm-1 HRMS(ESI) for C₁₆H₂₂N₁O₆ [M] Calcd: 339.13125 Found: 339.12933;HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, 1.0 mL/min, λ=254 nm,retention times: (major) 14.9 min, (minor) 20.6 min].

(2m) 78% yield; [α]_(D) ²⁰=+5.06 (c 0.33, CH₂Cl₂); ¹H NMR (300 MHz,CDCl₃) δ 7.34˜7.26 (d, J=23.9 Hz, 1H), 6.29˜6.28 (t, J=2.9, 1.6 Hz, 1H),6.22˜6.21 (d, J=3.0 Hz, 1H), 4.91˜4.88 (m, 2H), 4.39˜4.37 (m, 1H),4.25˜4.11 (m, 4H), 3.91˜3.88 (d, J=7.9 Hz, 1H), 1.28˜1.23 (t, J=7.1, 6.9Hz, 3H), 1.22˜1.17 (t, J=7.1, 6.9 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃)δ 167.35, 167.04, 149.74, 142.95, 110.74, 108.67, 75.64, 62.38, 53.20,37.03, 29.92, 14.17, 14.11 ppm; IR (KBr) 2985, 2940, 1734, 1559, 1506,1466, 1448; HRMS(ESI) for C₁₃H₁₈N₁O₇[M+H]⁺ Calcd: 300.10778 Found:300.10742; HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, 0.6 mL/min,λ=254 nm, retention times: (major) 22.7 min, (minor) 29.2 min].

(2n) [α]_(D) ²⁰=−24.29 (c 0.03, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.99(s, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.17˜7.14 (d, J=8.2 Hz, 2H), 4.20˜4.13(q, J=6.9, 6.9 Hz, 1H), 4.06˜3.97 (q, J=6.9 Hz, 1H), 3.77˜3.71 (m, 1H),3.50˜3.46 (d, J=10.1 Hz, 1H), 3.37˜3.31 (t, J=9.4, 9.4 Hz, 1H),1.23˜1.18 (t, J=7.1 Hz, 3H) ppm; HRMS(EI) for C₁₃H₁₅NO₃[M+H]⁺ Calcd:233.1052, Found: 233.1051.

(2o) [α]_(D) ²⁰=−24.29 (c 0.03, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 7.99(s, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.17˜7.14 (d, J=8.2 Hz, 2H), 4.20˜4.13(q, J=6.9, 6.9 Hz, 1H), 4.06˜3.97 (q, J=6.9 Hz, 1H), 3.77˜3.71 (m, 1H),3.50˜3.46 (d, J=10.1 Hz, 1H), 3.37˜3.31 (t, J=9.4, 9.4 Hz, 1H),1.23˜1.18 (t, J=7.1 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.15,169.30, 138.47, 133.51, 129.31, 128.67, 62.11, 55.65, 47.92, 44.04,14.35 ppm; IR (KBr) 3435, 3229, 3017, 2360, 1710, 1493 cm⁻¹; HRMS(ESI)for C₁₃H₁₄C₁N₀₃[M+H]⁺ Calcd: 267.06567, Found: 267.1026.

(2p) [α]_(D) ²⁰=+3.12 (c 2.33, MeOH); ¹H NMR (400 MHz, D₂θ) δ 7.27˜7.19(m, 5H), 3.21 (m, 2H), 3.11˜3.08 (d, 1H), 2.69 (dd, 1H, J=16.0, 6.0 Hz),2.59˜2.55 (dd, 1H, J=16.5, 8.5 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ175.29, 138.61, 129.57, 128.11, 44.10, 39.94, 38.35 ppm; HRMS(EI⁺) forC₉H₁₂C₁NO₂[M+HCl]⁺ Calcd: 201.0557, Found: 201.0563.

(2q) [α]_(D) ²⁰=−3.79 (c 2.33, H₂O); ¹H NMR (300 MHz, DMSO-d₆) δ 8.25(s, 3H), 7.35 (m, 4H), 3.08 (m, 1H), 2.92 (m, 2H), 2.57 (dd, J=9.5, 16.5Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d₆) δ 173.17, 141.20, 132.50,130.69, 129.36, 129.28, 128.59, 127.93, 44.15, 39.1, 38.66 ppm;HRMS(FAB⁺) for C₁₀H₁₂C₁NO₂[M+H]⁺ Calcd: 214.0635, Found: 214.0637.

(3a) [α]_(D) ²⁰ −18.5 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ7.91˜7.92 (m, 2H), 7.59˜7.26 (m, 8H), 4.85˜4.81 (dd, J=12.5, 6.7 Hz,1H), 4.71˜4.67 (dd, J=12.5, 7.8 Hz, 1H), 4.26˜4.20 (m, 1H), 3.51˜3.46(dd, J=17.7, 6.4 Hz, 1H), 3.45˜3.40 (dd, J=17.7, 7.5 Hz, 1H) ppm; ¹³CNMR (125 MHz, CDCl₃) δ 196.87, 139.15, 136.39, 133.60, 129.09, 128.77,128.04, 127.90, 127.48, 79.58, 41.54, 39.30 ppm; IR (KBr) 3058, 3029,2920, 1687, 1544, 1440, 1367, 1268, 1224, 1084, 988, 764, 703, 623, 559cm⁻¹; LRMS (ESI⁺) for C₁₆H₁₅NO₃ [M+Na]⁺ Calcd: 292.1, Found: 292.1; HPLC[Chiralcel AD-H, hexane/2-propanol=90/10, flow rate=1.0 mL/min, λ=254nm, retention times: (major) 12.8 min, (minor) 17.4 min]; R_(f) (SiO₂,EtOAc/n-hexane=1/5)=0.40

(3b) [α]_(D) ²⁰ −24.7 (c 1.0, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ7.92˜7.90 (m, 2H), 7.60˜7.57 (m, 1H), 7.48˜7.45 (m, 2H), 7.32˜7.29 (m,2H), 7.24˜7.22 (m, 2H), 4.83˜4.80 (dd, J=12.5, 6.5 Hz, 1H), 4.68˜4.64(dd, J=12.5, 8.1 Hz, 1H), 4.25˜4.19 (m, 1H), 3.48˜3.43 (dd, J=18.2, 6.4Hz, 1H), 3.43˜3.38 (dd, J=18.2, 7.3 Hz, 1H) ppm; ¹³C NMR (125 MHz,CDCl₃) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02,79.36, 41.36, 38.70 ppm; LRMS (ESI⁺) for C₁₆H₁₄C₁NO₃ [M+Na]⁺ Calcd:326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, flowrate=1.0 mL/min, λ=254 nm, retention times: (major) 24.3 min, (minor)37.5 min]; R_(f)(SiO₂, EtOAc/n-hexane=1/5)=0.31

(3c) [α]_(D) ²⁰ −19.4 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.91 (d,J=7.0 Hz, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.45 (t, J=8.0 Hz, 2H), 7.18˜7.13(m, 4H), 4.83˜4.79 (dd, J=12.5, 6.5 Hz, 1H), 4.68˜4.64 (dd, J=12.5, 8.0Hz, 1H), 4.22˜4.16 (m, 1H), 3.48˜3.44 (dd, J=17.5, 6.5 Hz, 1H),3.43˜3.38 (dd, J=18.0, 7.5 Hz, 1H), 2.31 (s, 3H) ppm; ¹³C NMR (125 MHz,CDCl₃) δ 196.96, 137.60, 136.42, 136.05, 133.56, 129.76, 128.75, 128.05,127.31, 79.73, 41.59, 38.96, 21.07 ppm; IR (KBr) 3058, 2922, 2862, 1685,1551, 1516, 1446, 1377, 1270, 1225, 998, 817, 755, 691, 551 cm⁻¹; LRMS(ESI⁺) for C₁₇H₁₇NO₃ [M+Na]⁺ Calcd: 306.1, Found: 306.2; HPLC [ChiralcelAD-H, hexane/2-propanol=90/10, flow rate=1.0 mL/min, λ=254 nm, retentiontimes: (major) 11.9 min, (minor) 16.3 min]; R_(f) (SiO₂,EtOAc/n-hexane=1/10)=0.33

(3d) [α]_(D) ²⁰ −25.8 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d,J=7.0 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.48˜7.45 (m, 4H), 7.18˜7.16 (m,2H), 4.83˜4.79 (dd, J=12.5, 6.5 Hz, 1H), 4.68˜4.64 (dd, J=12.5, 8.5 Hz,1H), 4.23˜4.17 (m, 1H), 3.48˜3.43 (dd, J=17.0, 6.5 Hz, 1H), 3.43˜3.38(dd, J=17.0, 7.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl₃) δ 196.47, 138.14,136.21, 133.74, 132.22, 129.24, 128.82, 128.02, 121.85, 79.28, 41.30,38.76 ppm; LRMS (ESI⁺) for C₁₆H₁₄BrNO₃ [M+Na]⁺ Calcd: 370.0, Found:370.1; HPLC [Chiralcel AD-H, hexane/2-propanol=90/10, flow rate=1.0mL/min, λ=254 nm, retention times: (major) 16.4 min, (minor) 22.4 min];R_(f)(SiO₂, EtOAc/n-hexane=1/5)=0.30

(3e) [α]_(D) ²⁰ −24.7 (c 1.0, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ7.92˜7.90 (m, 2H), 7.60˜7.57 (m, 1H), 7.48˜7.45 (m, 2H), 7.32˜7.29 (m,2H), 7.24˜7.22 (m, 2H), 4.83˜4.80 (dd, J=12.5, 6.5 Hz, 1H), 4.68˜4.64(dd, J=12.5, 8.1 Hz, 1H), 4.25˜4.19 (m, 1H), 3.48˜3.43 (dd, J=18.2, 6.4Hz, 1H), 3.43˜3.38 (dd, J=18.2, 7.3 Hz, 1H) ppm; ¹³C NMR (125 MHz,CDCl₃) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02,79.36, 41.36, 38.70 ppm; LRMS (ESI⁺) for C₁₆H₁₄C₁NO₃ [M+Na]⁺ Calcd:326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, flowrate=1.0 mL/min, λ=254 nm, retention times: (major) 24.3 min, (minor)37.5 min]; R_(f)(SiO₂, EtOAc/n-hexane=1/5)=0.31

(3f) [α]_(D) ²⁰ −20.2 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ7.93˜7.91 (m, 2H), 7.59˜7.44 (m, 3H), 7.20 (d, J=8.7 Hz, 2H), 6.86 (d,J=8.7, 2H), 4.82˜4.78 (dd, J=12.3, 6.7 Hz, 1H), 4.67˜4.63 (dd, J=12.3,7.9 Hz, 1H), 4.21˜4.15 (m, 1H), 3.78 (s, 3H), 3.47˜3.43 (dd, J=16.5, 6.5Hz, 1H), 3.43˜3.37 (dd, J=16.5, 6.6 Hz, 1H) ppm; ¹³C NMR (125 MHz,CDCl₃) δ 196.99, 159.10, 136.42, 133.56, 130.99, 128.75, 128.52, 128.04,114.45, 79.85, 55.27, 41.67, 38.65 ppm; LRMS (ESI⁺) for C₁₇H₁₇NO₄[M+Na]⁺ Calcd: 322.1, Found: 322.2; HPLC [Chiralcel AD-H,hexane/2-propanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retentiontimes: (major) 11.8 min, (minor) 16.0 min]; R_(f)(SiO₂,EtOAc/n-hexane=1/5)=0.31

(3g) [α]_(D) ²⁰ −5.2 (c 1.4, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.94˜7.92(m, 2H), 7.58˜7.55 (m, 1H), 7.47˜7.44 (m, 2H), 7.26˜7.20 (m, 2H),6.92˜6.88 (m, 2H), 4.89˜4.82 (m, 2H), 4.45˜4.39 (m, 1H), 3.86 (s, 3H),3.54 (d, J=7.5 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl₃) δ 197.64, 157.20,136.63, 133.38, 129.52, 128.99, 128.68, 128.05, 126.70, 120.96, 110.05,77.90, 55.38, 39.80, 35.95 ppm; IR (KBr) 3063, 2923, 2852, 1684, 1598,1550, 1494, 1445, 1377, 1246, 1120, 1025, 754, 690 cm⁻¹; LRMS (ESI⁺) forC₁₇H₁₇NO₄ [M+Na]⁺ Calcd: 322.1, Found: 322.2; HPLC [Chiralcel AD-H,hexane/2-propanol=85/15, flow rate=1.0 mL/min, λ=254 nm, retentiontimes: (major) 9.4 min, (minor) 12.7 min]; R_(f)(SiO₂,EtOAc/n-hexane=1/5)=0.30

(3h) [α]_(D) ²⁰ −12.9 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ7.96˜7.94 (m, 2H), 7.61˜7.58 (m, 1H), 7.49˜7.46 (m, 2H), 7.34 (m, 1H),6.30˜6.29 (m, 1H), 6.19 (d, J=3.3 Hz, 1H), 4.83˜4.79 (dd, J=11.6, 5.4Hz, 1H), 4.77˜4.73 (dd, J=11.6, 6.0 Hz, 1H), 4.36˜4.31 (m, 1H),3.55˜3.50 (dd, J=17.7, 6.1 Hz, 1H), 3.46˜3.41 (dd, J=17.7, 7.3 Hz, 1H)ppm; ¹³C NMR (125 MHz, CDCl₃) δ 196.55, 151.95, 142.32, 136.26, 133.69,128.80, 128.07, 110.53, 107.20, 77.27, 38.99, 33.19 ppm; IR (KBr) 3121,3062, 2918, 1685, 1596, 1553, 1505, 1448, 1377, 1213, 1183, 1012, 917,749, 691, 599 cm⁻¹; LRMS(ESI⁺) for C₁₄H₁₃NO₄ [M+Na]⁺ Calcd: 282.1,Found: 282.1; HPLC [Chiralcel AD-H, hexane/2-propanol=95/5, flowrate=1.0 mL/min, λ=254 nm, retention times: (major) 12.9 min, (minor)15.6 min]; R_(f) (SiO₂, EtOAc/n-hexane=1/5)=0.32

(3i) ¹H NMR (500 MHz, CDCl₃) δ 7.38˜7.16 (m, 8H), 6.87˜6.85 (m, 2H),4.75˜4.71 (dd, J=11.6, 6.6 Hz, 1H), 4.68˜4.64 (dd, J=11.6, 6.4 Hz, 1H),4.10˜4.04 (m, 1H), 3.04˜3.0 (dd, J=13.7, 4.6 Hz, 1H), 2.99˜2.94 (dd,J=13.7, 5.6 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 169.33, 150.33,137.96, 129.50, 129.22, 128.29, 127.55, 126.12, 121.39, 79.38, 40.38,37.87 ppm; LRMS (ESI⁺) for C₁₆H₁₅NO₄ [M+Na]⁺ Calcd: 308.1, Found: 308.1;R_(f)(SiO₂, EtOAc/n-hexane=1/5)=0.40.

(3j) ¹H NMR (500 MHz, CDCl₃) δ 7.35˜7.22 (m, 7H), 6.92˜6.90 (m, 2H),4.79˜4.75 (dd, J=12.7, 7.3 Hz, 1H), 4.71˜4.67 (dd, J=12.7, 7.9 Hz, 1H),4.11˜4.06 (m, 1H), 3.08˜3.03 (dd, J=14.7, 5.3 Hz, 1H), 3.01˜2.96 (dd,J=14.7, 6.5 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 169.01, 150.17,136.37, 134.23, 129.53, 129.43, 128.88, 126.20, 121.26, 79.08, 39.70,37.67 ppm; LRMS (ESI⁺) for C₁₆H₁₄C₁NO₄ [M+Na]⁺ Calcd: 342.1, Found:342.1; R_(f)(SiO₂, EtOAc/n-hexane=1/5)=0.31.

(3k) [α]_(D) ²⁰=+36.0 (c 0.01, CHCl₃)

(3l) [α]_(D) ²⁰=−36.4 (c 0.01, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ7.37˜7.33 (m, 2H), 7.29˜7.27 (m, 2H), 7.26˜7.25 (m, 1H), 5.92 (br s,1H), 3.81˜3.77 (m, 1H), 3.71 (q, J=8.0 Hz, 1H), 3.45˜3.41 (dd, J=9.4,2.0 Hz, 1H), 2.77˜2.72 (dd, J=16.8, 8.7 Hz, 1H), 2.54˜2.49 (dd, J=17.0,8.5 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 177.93, 142.14, 128.88,127.13, 126.79, 49.60, 40.31, 38.02 ppm; LRMS (ESI⁺) for C₁₀H₁₁NO[M+H]⁺Calcd: 162.10, Found: 162.20.

(3m) [α]_(D) ²²=+33.0 (c 1.0, EtOH)

(3n) [α]_(D) ³⁰=−39.7 (c 1.00, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.32(d, J=8.5 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 5.72 (br s, 1H), 3.80˜3.77(m, 1H), 3.69 (q, J=8.5 Hz, 1H), 3.40˜3.36 (dd, J=8.4, 2.5 Hz, 1H),2.77˜2.71 (dd, J=17.8, 8.5 Hz, 1H), 2.48˜2.43 (dd, J=16.9, 8.5 Hz, 1H)ppm; ¹³C NMR (125 MHz, CDCl₃) δ 177.68, 140.59, 132.93, 129.03, 128.15,49.49, 39.66, 37.90 ppm; HRMS (ESI⁺) for C₁₀H₁₀ClNO [M+H]⁺ Calcd:196.0445, Found: 196.1160.

(3o) [α]_(D) ²⁵=+5.8 (c 0.5, H₂O); ¹H NMR (500 MHz, D₂O) δ 7.47˜7.44 (m,2H), 7.41˜7.36 (m, 3H), 3.47˜3.36 (m, 2H), 3.27 (t, J=11.0 Hz, 1H),2.89˜2.85 (dd, J=16.0, 5.9 Hz, 1H), 2.81˜2.76 (dd, J=16.0, 8.8 Hz, 1H)ppm; ¹³C NMR (125 MHz, D₂θ) δ 175.62, 138.37, 129.37, 128.30, 127.87,43.81, 40.0, 38.34 ppm; LRMS (ESI⁺) for C₁₀H₁₃NO₂[M+H]⁺ Calcd: 180.1,Found: 180.2; R_(f)(SiO₂, CH₂Cl₂/MeOH=10/1)=0.48.

(3p) [α]_(D) ²⁵=+1.8 (c 0.5, H₂O); ¹H NMR (500 MHz, D₂O) δ 7.40˜7.37 (m,2H), 7.29˜7.26 (m, 2H), 3.39˜3.30 (m, 2H), 3.22˜3.16 (m, 1H), 2.81˜2.76(dd, J=16.1, 5.9 Hz, 1H), 2.70˜2.65 (dd, J=16.1, 8.9 Hz, 1H) ppm; ¹³CNMR (125 MHz, D₂O) δ 175.46, 137.02, 133.38, 129.41, 129.25, 43.60,39.47, 38.33 ppm; HRMS (FAB⁺) for C₁₀H₁₂C₁NO₂ [M+H]⁺ Calcd: 214.0635,Found: 214.0627; R_(f) (SiO₂, CH₂Cl₂/MeOH=10/1)=0.46.

(3q) [α]_(D) ²⁰=−8.4 (c=3.0, MeOH)

(3r) [α]_(D) ²⁰=+8.5 (c=3.0, MeOH); ¹H NMR spectrum (CDCl₃), δ, ppm:2.59 d.d (1H, 3-H, 3JHH=8.4, 2JHH=17.0 Hz), 2.81 d.d (1H, 3-H, 3JHH=8.4,2JHH=17.0 Hz), 3.53 m (1H, 5-H), 3.63 m (1H, 4-H), 3.85 m (1H, 5-H),3.97 d.d (2H, NCH2CO, 3JHH=16.3, 2JHH=33.0 Hz); 6.24 br.s and 6.66 br.s(1H each, NH2), 7.22˜7.31 m (5H, Ph). ¹³C NMR spectrum (CDCl₃), δ, ppm:37.48, 38.54, 46.25, 55.55, 126.89, 127.27, 129.01, 141.97, 170.78,175.03 pp; HRMS (ESI⁺) for C₁₀H₁₃NO₂ [M+Na]⁺ Calcd: 241.0957, Found:241.0947.

(3s) [α]_(D) ²⁵=−62.0 (c 1.0, MeOH); ¹H NMR (CDCl₃, 500 MHz) 6.51 (s,1H) 5.93 (s, 1H) 4.46 (dd, J=8.9, 7.9, 1H) 3.47 (dd, J=9.8, 7.8 Hz, 1H)3.05 (dd, J=9.8, 7.1 Hz, 1H) 2.54 (dd, J=16.7, 8.6, 1H) 2.39˜2.23 (m,1H) 2.06 (dd, J=16.7, 8.1, 1H) 1.99˜1.85 (m, 1H) 1.70˜1.62 (m, 1H)1.45˜1.37 (m, 2H) 1.37˜1.25 (m, 2H) 0.94˜0.84 (m, 6H) ppm; ¹³C NMR(CDCl₃, 100 MHz) 175.4, 172.6, 55.7, 49.4, 37.8, 36.4, 31.9, 21.2, 20.5,13.9, 10.4 ppm; HRMS calculated for [M+Na]⁺ C₁₁H₂₀O₂N₂ 235.1422, found235.1418.

Example 3: Reaction Test Results when Different Chiral Organocatalystsand Different Solvents were Used

The Michael addition reaction described in Example 2 was carried outusing each of the chiral organocatalysts prepared in Example 1 in wateror toluene as the solvent (FIG. 6 and Tables 3 and 4). The reactiontimes and yields were investigated.

TABLE 3 Chiral organocatalyst R₁ R₂ Solvent Time (h) Yield (%)^(b) ee(%)^(e) 1d Me H Water^(a) 14 97 99 1d Me H Toluene 96 89 80 1j Me HWater 10 98 99 1k Me H Water 19 95 94 1j Et H Water 12 97 99 1j Et HToluene 96 81 80 1l Et H Water 12 81 94 1l Et H Toluene 96 86 93 1j Bn HWater 14 93 98 1k Bn H Water 26 91 98 (^(a)5 equiv., ^(b)Isolated yield,^(c)ee values were decided by chiral phase HPLC using an AD-H or OD-Hcolumn)

TABLE 4 Chiral organocatalyst R₁ R₂ Solvent Time (min) Yield (%)^(b) ee(%)^(e) 1m Et H — 60 97 91 1n Et H — 60 95 99 1m Et H Water 5 99 99 1mEt Et Water 30 95 99 1n Et H Water 60 96 90 1m Bn H Water 15 94 99 1n BnH Water 60 92 99 1m Et Br Water 10 95 99 1n Et Br Water 90 96 99 (^(a)5equiv., ^(b)Isolated yield, ^(c)ee values were decided by chiral phaseHPLC using an AD-H or OD-H column)

These results reveal that the trifluoromethyl-substituted chiralorganocatalysts can be used in water, indicating that the interactionbetween the fluorine atoms in water reduces the activation barrier.

Example 4: Reaction Test Results when Different α,β-Unsaturated NitroCompounds were Used

The Michael addition reaction described in Example 2 was carried outwith each of the α,β-unsaturated nitro compounds shown in Table 5 usingthe chiral organocatalyst 1m prepared in Example 1 in water as thesolvent. The reaction times and yields were investigated. Specifically,trans-β-nitrostyrene (1.0 equiv.), malononitrile (2.0 equiv.), and0.1˜0.001 mol % of the chiral organocatalyst 1m were added to water (0.4ml). The mixture was stirred at room temperature (rt). The reactionconversion was monitored by TLC. After completion of the reaction, ethylacetate (0.2 ml) was added to the reaction mixture. This solution waswashed twice with water (2×1.0 mL), dried over magnesium sulfate, andconcentrated to afford the desired product. The product was purified bychromatography on a silica-gel column (hexane/methylene chloride, 2:1)(FIG. 7 and Table 5).

TABLE 5 R₁ R₂ Ar Time (h) Yield (%)^(b)) ee (%)^(c)) 1 Me Me Ph 24 98 992 Et Et Ph 24 98 99   3^(d)) Et Et Ph 0.5 98 99  4^(e)) Et Et Ph 6 98 995 i-Pr i-Pr Ph 24 96 99 6 n-Pr n-Pr Ph 24 96 99 7 Bu Bu Ph 24 99 99 8 EtEt 4-Br—Ph 24 94 99 9 Et Et 4-Cl—Ph 24 95 99 10  Et Et 4-Me—Ph 24 91 9311  Et Et 4-OMe—Ph 24 93 91 12  Et Et 2-OMe—Ph 24 91 96 13  Et Et4-OH—Ph 24 95 96 14  Et Et furyl 24 97 99 (^(b))Isolated yield, ^(c))eevalues were decided by chiral phase HPLC, ^(d))reaction in 0.1 mol %catalyst, ^(e))reaction in 0.01 mol % catalyst)

Example 5: Reaction Test Results when Different α,β-Unsaturated Ketone(Trans-Chalcone) Compounds were Used

The Michael addition reaction described in Example 2 was carried outwith each of the nitroethyl esters shown in Table 6 was carried outusing the chiral organocatalyst 1m prepared in Example 1 and water asthe solvent. The reaction times and yields were investigated.Specifically, an α,β-unsaturated ketone (1.0 equiv.), the nitroethylester (2.0 equiv.), and 0.1˜0.009 mol % of the chiral organocatalyst 1mwere added to water (0.4 ml). The mixture was stirred at roomtemperature (rt). The reaction conversion was monitored by TLC. Aftercompletion of the reaction, sodium hydroxide (1.0 equiv.) and ethanolwere added to the reaction mixture, followed by stirring at roomtemperature for 12 h. The resulting mixture was concentrated in vacuo toafford the desired product. The product was purified by chromatographyon a silica-gel column (hexane/ethyl acetate, 10:1) (FIG. 8 and Table6).

TABLE 6 Ar Time (h) Yield (%)^(b)) ee (%)^(c)) 1 C₆H₅ 24 85 99 24-MeC₆H₄ 24 82 88 3 4-BrC₆H₄ 24 83 92 4 4-ClC₆H₄ 24 80 92 5 4-MeOC₆H₄ 2478 94 6 2-MeOC₆H₄ 24 75 82 7 2-furyl 24 83 98 (^(b))Isolated yield,^(c))ee values were decided by chiral phase HPLC)

General Experimental Methods

IR spectra were recorded on a NICOLET 380 FT-IR spectrophotometer.Optical rotations were performed with a Rudolph Automatic polarimeter(model name: A20766 APV/6w). ¹H NMR spectra were recorded on a VarianMercury 400 (400 MHz) or Varian Mercury 300 (300 MHz) with TMS as aninternal reference. ¹³C NMR spectra were recorded on a Varian Mercury400 (400 MHz) with TMS or CDCl₃ as an internal reference. Chiral HPLCanalysis was performed on a Jasco LC-1500 Series HPLC system with a UVdetector. All experiments were performed in oven-dried glass flasksunder an argon atmosphere. Toluene (CaH₂) and THF (Na, benzophenone)were dried by distillation before use.

Although the particulars of the present invention have been described indetail, it will be obvious to those skilled in the art that suchparticulars are merely preferred embodiments and are not intended tolimit the scope of the present invention. Therefore, the substantialscope of the present invention is defined by the appended claims andtheir equivalents.

INDUSTRIAL APPLICABILITY

The chiral bifunctional organocatalyst of the present invention ishighly enantioselective and can be easily synthesized. The use of thechiral organocatalyst enables the production of γ-amino acids with highenantioselectivity in high yield in an economical and simple manner. Inaddition, even a small amount of the chiral organocatalyst is sufficientfor mass production of various unnatural γ-amino acids with Rconfiguration in high optical purity. Therefore, the chiralorganocatalyst of the present invention can be widely utilized invarious industrial fields, including the pharmaceutical industry.

1. A chiral organocatalyst represented by Formula 1:

wherein X is selected from O, S, P—R₃, and N—R₄ and R₁ to R₄ areidentical to or different from each other and are each independentlyselected from hydrogen, deuterium, substituted or unsubstituted C₁-C₃₀alkyl, substituted or unsubstituted C₂-C₃₀ heteroaryl, substituted orunsubstituted C₆-C₃₀ aryl.
 2. The chiral organocatalyst according toclaim 1, wherein R₁ in Formula 1 is hydrogen, 3-pentyl, Ph₂CH or3,5˜(CF₃)₂-PhCH₂ and R₂ in Formula 1 is phenyl, 3,5-(CF₃)₂-Ph, p-tolyl,4-CF₃-Ph, C₆F₅, 4-NO₂-Ph, 4-CN-Ph, 4-F-Ph, t-butyl or 3,5˜(Me)₂-Ph. 3.The chiral organocatalyst according to claim 1, wherein the chiralorganocatalyst represented by Formula 1 is selected from the followingcompounds:


4. A method for preparing a chiral organocatalyst represented by Formula1:

wherein X is selected from O, S, P—R₃, and N—R₄ and R₁ to R₄ areidentical to or different from each other and are each independentlyselected from hydrogen, deuterium, substituted or unsubstituted C₁-C₃₀alkyl, substituted or unsubstituted C₂-C₃₀ heteroaryl, substituted orunsubstituted C₆-C₃₀ aryl, the method comprising reacting(R,R)-1,2-diphenylethylenediamine (DPEN) represented by Formula 2:

with a thiourea.
 5. The method according to claim 4, wherein R₁ inFormula 1 is hydrogen, 3-pentyl, Ph₂CH or 3,5˜(CF₃)₂-PhCH₂ and R₂ inFormula 1 is phenyl, 3,5˜(CF₃)₂-Ph, p-tolyl, 4-CF₃-Ph, C₆F₅, 4-NO₂-Ph,4-CN-Ph, 4-F-Ph, t-butyl or 3,5˜(Me)₂-Ph.
 6. The method according toclaim 4, wherein the chiral organocatalyst represented by Formula 1 isselected from the following compounds:


7. A method for producing an unnatural γ-amino acid, comprisingperforming a Michael addition reaction of an α,β-unsaturated nitrocompound with a dialkyl malonic acid or malononitrile in the presence ofthe chiral organocatalyst according to claim 1 by the following reaction1:

wherein A and B are identical to or different from each other and areeach independently selected from hydrogen, deuterium, nitro, cyano,substituted or unsubstituted C₁-C₃₀ ketone, substituted or unsubstitutedC₁-C₃₀ ester, substituted or unsubstituted C₁-C₃₀ alkyl, substituted orunsubstituted C₃-C₃₀ cycloalkyl, substituted or unsubstituted C₂-C₃₀heteroaryl, substituted or unsubstituted C₆-C₃₀ aryl, substituted orunsubstituted C₁-C₃₀ alkoxy, and R₅ and R₆ are identical to or differentfrom each other and are each independently selected from hydrogen,deuterium, nitro, halogen, cyano, substituted or unsubstituted C₁-C₃₀ketone, substituted or unsubstituted C₁-C₃₀ ester, substituted orunsubstituted C₁-C₃₀ alkyl, substituted or unsubstituted C₃-C₃₀cycloalkyl, substituted or unsubstituted C₂-C₃₀ heteroaryl, substitutedor unsubstituted C₆-C₃₀ aryl, substituted or unsubstituted C₁-C₃₀alkoxy.
 8. The method according to claim 7, wherein the Michael additionreaction is performed in the absence or presence of water or an organicsolvent.
 9. The method according to claim 8, wherein the Michaeladdition reaction is performed in the absence or presence of water. 10.The method according to claim 7, wherein the Michael addition reactionaffords a nitrostyrene.
 11. The method according to claim 7, furthercomprising synthesizing a pyrrolidinone from the Michael adduct whereinthe pyrrolidinone is represented by Formula 3-1 or 3-2:

wherein R₇ and R₈ are identical to or different from each other and areeach independently selected from hydrogen, deuterium, nitro, halogen,cyano, substituted or unsubstituted C₁-C₃₀ ketone, substituted orunsubstituted C₁-C₃₀ ester, substituted or unsubstituted C₁-C₃₀ alkyl,substituted or unsubstituted C₃-C₃₀ cycloalkyl, substituted orunsubstituted C₂-C₃₀ heteroaryl, substituted or unsubstituted C₆-C₃₀aryl, substituted or unsubstituted C₁-C₃₀ alkoxy,

wherein R₇ and R₈ are as defined in Formula 3˜1.
 12. The methodaccording to claim 11, further comprising treating the pyrrolidinonewith hydrochloric acid to produce an unnatural γ-amino acid representedby Formula 4-1 or 4-2:

wherein R₉ is selected from hydrogen, deuterium, nitro, halogen, cyano,substituted or unsubstituted C₁-C₃₀ ketone, substituted or unsubstitutedC₁-C₃₀ ester, substituted or unsubstituted C₁-C₃₀ alkyl, substituted orunsubstituted C₃-C₃₀ cycloalkyl, substituted or unsubstituted C₂-C₃₀heteroaryl, substituted or unsubstituted C₆-C₃₀ aryl, substituted orunsubstituted C₁-C₃₀ alkoxy,

wherein R₉ is as defined in Formula 4-1.